Pathological mitochondrial dysfunction mimics an aging pathway in budding yeast

Mitochondrial dysfunction is widely considered a conserved hallmark of aging and has been linked to lifespan limitation across many species, including the budding yeast Saccharomyces cerevisiae. However, the widely used S288C laboratory background carries several polymorphisms that impair mitochondrial genome stability and function. Here, using a three-color reporter and single-cell microfluidics, we demonstrate how these mutations cause spontaneous transition to a state with severe mitochondrial deficiency characterized by low membrane potential, loss of heme biosynthesis, activation of iron regulon and morphological changes. Equally affecting young and old cells, this condition-dependent transition creates an apparent split in aging trajectories mimicking an age-dependent pathway. We further identify the BY allele of the MKT1 gene as a major genetic driver of this pathological mitochondrial state. Finally, we show that condition-dependent variation in petite formation contributes to lifespan differences in BY. Together, our results indicate that background-specific pathological defects can distort apparent aging trajectories and obscure genuine age-associated phenotypes.